Gastrointestinally active thioureas

ABSTRACT

Thioureas of the general structure ArylNHC(S)-NR1R2 are useful as antidiarrheal, antimotility or antisecretory agents. Particularly useful are those wherein Aryl is 2-methylphenyl and NR1R2 is NHCH2CH2OH.

This application is a continuation-in-part of copending U.S. applicationSer. No. 374,852 filed June 29, 1973, now abandoned, which was adivisional of U.S. Ser. No. 175,373, filed Aug. 26, 1971, now abandoned.

This invention is concerned with the discovery that certain substitutedthioureas have valuable pharmacological properties. Specifically thereis provided a new class of structures which have gastrointestinalactivity as antimotility, antidiarrheal and antisecretory agents.

Pharmacological studies employing rats and mice as the experimentalanimals indicate that the instant products and compositions containingthe active products are effective antisecretory, antispasmodic oranticholinergic agents which can be used in the treatment ofgastrointestinal disorders. When administered in effective therapeuticaldosages in conventional vehicles, the instant products are useful intreating gastrointestinal disturbances.

In accordance with the present invention, there is employed an activeingredient having the following formula: ##EQU1## wherein R¹ is hydrogenor lower alkyl such as methyl and the like; R² is lower alkyl such asmethyl and the like or a radical of the formula --CH₂ CH₂ Y wherein Y isamino dimethyl amino or hydroxy; X is lower alkyl such as methyl, ethyland the like, halo, such as, bromo, chloro and the like or lower alkoxysuch as methoxy and the like and m is an integer of 0 to 3.

A preferred embodiment of this invention relates to active products andcompositions having as their active ingredients thioureas of theformula: ##EQU2## wherein X¹ is methyl or ethyl; X² is methyl, chloro orbromo and m is an integer of 0 to 2.

These thioureas are either known in the art or may be prepared bymethods well known to those skilled in the art for example by theaddition of a primary or secondary amine, to an aryl isothiocyanate asillustrated by the following formula: ##EQU3## where R¹, R², X and m areas defined above.

Other methods of preparation are reviewed by Schroeder in ChemicalReviews 55, 181 (1955).

Schroeder in Chem. Reviews 55, 183-189 (1955) discusses the biologicalproperties of thioureas. Specifically discussed are antitubercular,antithyroid, hypnotic, anesthetic, anthelmintic, antibacterial,antiphenoloxidase, insecticidal and rodenticidal properties.Gastrointestinal activity of the type described is not mentioned in thissurvey paper.

The preparation of 1-(2, 4-dimethylphenyl)-3-(2-hydroxyethyl)thiourea isgiven below as a typical method of preparation for these compounds.

The compositions containing the thioureas as the active ingredient andalso the thioureas (I) themselves are effective as antimotility,antidiarrheal or antisecretory agents which can be administered in awide variety of therapeutic dosages in conventional vehicles, forexample, oral administration in the form of a tablet or capsules, oralsolutions or suspensions or as suppositories. Also, the daily dosage ofthe product may be varied over a wide range varying from 50 to 2,000milligrams. The product is preferably administered in subdivided dosagesin the form of oral solutions. An effective amount of the drug isordinarily supplied at a dosage level of from about 0.1 ml. to about 1.0ml./kg. of body weight. Preferably the range is from about 0.2 ml. toabout 0.5 ml./kg. body weight. These dosages are well below the toxic orlethal dose of the products.

Tablets may be prepared by mixing the active ingredient withconventional tabletting ingredients such as calcium phosphate, lactose,corn starch, magnesium stearate and the like. The liquid forms in whichthe active ingredients may be incorporated include suitable flavoredsuspending or dispersing agents such as synthetic or natural gums, forexample, tragacanth, acacia, methylcellulose and the like. Otherdispersing agents which may be employed include glycerin, castor oil andthe like. For parenteral adminstration sterile suspensions and solutionsmay be desired.

It is also within the scope of this invention to combine two or more ofthe compounds in this invention in a unit dosage form or to combine oneor more of the compounds of this invention with known antimotility,antidiarrheal or antisecretory agents.

The following example is illustrative of how to prepare the compounds ofthis invention. However, said examples are merely illustrative andshould not be construed as limiting the scope of the invention.

1-(2,4-Dimethylphenyl)-3-(2-hydroxyethyl)-thiourea

To 20 g. (0.12 mole) of 2,4-dimethylphenylisothiocyanate in 30 ml. ofacetone was added dropwise 10 g. (0.16 mole) of ethanolamine in 20 ml.acetone. The solution was refluxed 1 hour then cooled to 4° C., to givecrystals which were filtered off, washed with cold ethanol and dried toafford 1-(2,4-dimethylphenyl)-3-(2-hydroxyethyl)-thiourea, 16.8 g. (54%yield) of white crystals m.p. 137.5°-139° C.

Specific structures which were examined in this study are included inTable I.

                  Table I                                                         ______________________________________                                        ArylNHC(S)NR.sup.1 R.sup.2 Structures                                         Preparation                                                                             Aryl           NR.sup.1 R.sup.2                                     ______________________________________                                        A         2-CH.sub.3 C.sub.6 H.sub.4                                                                   NHCH.sub.2 CH.sub.2 OH                               B         2-C.sub.2 H.sub.5 C.sub.6 H.sub.4                                                            NHCH.sub.2 CH.sub.2 OH                               C         2-isoC.sub.3 H.sub.7 C.sub.6 H.sub.4                                                         NHCH.sub.2 CH.sub.2 OH                               D         4-CH.sub.3 C.sub.6 H.sub.4                                                                   NHCH.sub.2 CH.sub.2 OH                               E         2,3-(CH.sub.3).sub.2 C.sub.6 H.sub.3                                                         NHCH.sub.2 CH.sub.2 OH                               F         2,4-(CH.sub.3).sub.2 C.sub.6 H.sub.3                                                         NHCH.sub.2 CH.sub.2 OH                               G         2,5-(CH.sub.3).sub.2 C.sub.6 H.sub.3                                                         NHCH.sub.2 CH.sub.2 OH                               H         2,6-(CH.sub.3).sub.2 C.sub.6 H.sub.3                                                         NHCH.sub.2 CH.sub.2 OH                               I         3,4-(CH.sub.3).sub.2 C.sub.6 H.sub.3                                                         NHCH.sub.2 CH.sub.2 OH                               J         3,5-(CH.sub.3).sub.2 C.sub.6 H.sub.3                                                         NHCH.sub.2 CH.sub.2 OH                               K         2-CH.sub.3 -3-ClC.sub.6 H.sub.3                                                              NHCH.sub.2 CH.sub.2 OH                               L         2-CH.sub.3 -4-ClC.sub.6 H.sub.3                                                              NHCH.sub.2 CH.sub.2 OH                               M         2-CH.sub.3 -5-ClC.sub.6 H.sub.3                                                              NHCH.sub.2 CH.sub.2 OH                               N         2-CH.sub.3 -6-ClC.sub.6 H.sub.3                                                              NHCH.sub.2 CH.sub.2 OH                               O         2-CH.sub.3 -4-BrC.sub.6 H.sub.3                                                              NHCH.sub.2 CH.sub.2 OH                               P         2,4-Cl.sub.2 C.sub.6 H.sub.3                                                                 NHCH.sub.2 CH.sub.2 OH                               Q         2-CH.sub.3 -4-HOC.sub.6 H.sub.3                                                              NHCH.sub.2 CH.sub.2 OH                               R         2-CH.sub.3 -4-CH.sub.3 OC.sub.6 H.sub.3                                                      NHCH.sub.2 CH.sub.2 OH                               S         2,4,6-(CH.sub.3).sub.3 C.sub.6 H.sub.2                                                       NHCH.sub.2 CH.sub.2 OH                               T         α-naphthyl                                                                             NHCH.sub.2 CH.sub.2 OH                               U         β-naphthyl                                                                              NHCH.sub.2 CH.sub.2 OH                               AA        2-CH.sub.3 C.sub.6 H.sub.4                                                                   N(CH.sub.3).sub.2                                    AB        2,4-(CH.sub.3).sub.2 C.sub.6 H.sub.3                                                         N(CH.sub.3).sub.2                                    AC        2,6-(CH.sub.3).sub.2 C.sub.6 H.sub.3                                                         N(CH.sub.3).sub.2                                    AD        2-CH.sub.3 -4-ClC.sub.6 H.sub.3                                                              N(CH.sub.3).sub.2                                    AE        2,4-(CH.sub.3).sub.2 C.sub.6 H.sub.3                                                         NHCH.sub.3                                           AF        2,4-(CH.sub.3).sub.2 C.sub.6 H.sub.3                                                         NHC.sub.2 H.sub.5                                    AG        2,4-(CH.sub.3).sub.2 C.sub.6 H.sub.3                                                         NHCH.sub.2 CH.sub.2 NH.sub.2                         AH        2,4-(CH.sub.3).sub.2 C.sub.6 H.sub.3                                                         NHCH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                AI        2,6-(CH.sub.3).sub.2 C.sub.6 H.sub.3                                                         NHCH.sub.2 CH.sub.2 NH.sub.2                         AJ        2-CH.sub.3 -4-ClC.sub.6 H.sub.3                                                              NHCH.sub.2 CH.sub.2 NH.sub.2                         AK        2,4-(CH.sub.3).sub.2 C.sub.6 H.sub.3                                                         NHCH.sub.2 CH.sub.2 SH                               AL        2,4-(CH.sub.3).sub.2 C.sub.6 H.sub.3                                                         N(CH.sub.3) CH.sub.2 CH.sub.2 OH                     AM        2,4-(CH.sub.3).sub.2 C.sub.6 H.sub.3                                                         N(CH.sub.2 CH.sub.2 OH).sub.2                        AN        2,4-(CH.sub.3).sub.2 C.sub.6 H.sub.3                                                         NHCH(CH.sub.3)CH.sub.2 OH                            AO        2,4-(CH.sub.3).sub.2 C.sub.6 H.sub.3                                                         NHC(CH.sub.3).sub.2 CH.sub.2 OH                      AP        2,4-(CH.sub.3).sub.2 C.sub.6 H.sub.3                                                         NHCH.sub.2 CH(CH.sub.3)OH                            AQ        2,4-(CH.sub.3).sub.2 C.sub.6 H.sub.3                                                         NHCH.sub.2 CH.sub.2 CH.sub.2 OH                      AR        (2,6-(CH.sub.3).sub.2 C.sub.6 H.sub.3 NHC(O)NHCH.sub.2 CH.sub.2               OH)                                                                 ______________________________________                                    

The gastrointestinal activity of the compounds of this invention wasdetermined by evaluation in three types of tests, antisecretory,antimotility and antidiarrheal.

ANTISECRETORY

Test procedure of Shay, Komoarov, Fels, Merance, Gruenstein and Spiletin Gastroenterology 5, 43 (1945) and Ishii in Jap. J. Pharmacology 19,125 (1969). Adult female Wistar rats weighing 140 to 160 g. were starvedfor 24 hours prior to the test. The animals were anaesthetized withether, shaved on the abdomen, and a small midline incision made. Thepylorus was exposed, ligated, and the wound subsequently closed withwound clips. The animals were treated with the test compoundadministered either orally 1 hour prior to pyloric ligation orsubcutaneously immediately after ligation. The test compound wasadministered in distilled water or 0.5% methyl cellulose. Six animalswere used for each treatment. Five hours following the ligation, theanimals were sacrificed, the stomachs were carefully removed and opened,and the gastric contents measured for volume and titratable acidity. Theresults are reported in terms of an ED₅₀, i.e., the dosage in mg./kg.which caused a 50% reduction in the volume of gastric secretion in thetreated rats when compared to the controls. A maximum dosage of 10mg./kg. was used for the test compounds. A result comparable to theuntreated controls was reported as "N", i.e., inactive.

The results are given in Table II.

                  Table II                                                        ______________________________________                                        Antisecretory Activity                                                        Preparation                                                                           ED.sub.50 (mg./kg.)                                                                       Preparation ED.sub.50 (mg./kg.)                           ______________________________________                                        A         3-10      AA          N                                             B         >10       AB          N                                             C         N         AC          N                                             D         NT*       AD          N                                             E         3         AE          N                                             F         0.5-1     AF          N                                             G         N         AG          N                                             H         0.5-1     AH          N                                             I         N         AI          N                                             J         >10       AJ          N                                             K         >10       AK          N                                             L         1-3       AL          >10                                           M         >10       AM          N                                             N         N         AN          N                                             O         <10       AO          N                                             P         N         AP          >10                                           Q         N         AQ          N                                             R         N         AR          N                                             S         <10       atropine    8.0                                           T         NT        Daricon     2.4                                           U         N         Pro-Banthine                                                                              8.0                                           ______________________________________                                         *NT = not tested                                                         

The compounds found to be active in the antisecretory test include:2-CH₃ C₆ H₄ NHC(S)NHCH₂ CH₂ OH; 2,3-(CH₃)₂ -C₆ H₃)₂ C₆ H₃ NHC(S)NHCH₂CH₂ OH; 2,4-(CH₃)₂ C₆ H₃ NHC(S)NHCH₂ CH₂ OH; 2,6-(CH₃)₂ C₆ H₃NHC(S)NHCH₂ CH₂ OH; 2-CH₃ -4-ClC₆ H₃ NHC(S)NHCH₂ -CH₂ OH and2,4,6-(CH₃)₃ C₆ H₂ NHC(S)NHCH₂ CH₂ OH.

ANTIMOTILITY

The method used to measure antimotility is adopted from Janssen andJageneau, J. Pharmacy and Pharmacology 9, 381 (1957). Adult male miceweighing in the range of 20 to 30 g. were starved for 24 hours prior tothe test. The animals were then treated orally with the test compounddissolved in water or suspended in methyl cellulose. One hour later,each animal was dosed with 0.2 ml. of a charcoal suspension consistingof 5% activated charcoal suspended in 0.25% methyl cellulose. Theanimals were sacrificed 3.5 hours after the charcoal administration andtheir cecums examined for the presence or absence of charcoal. Underthese conditions charcoal appears in the cecum of greater than 90% ofplacebo-treated animals used as controls. The results are reported interms of an ED₅₀, i.e., the dosage in mg./kg. which prevented thecharcoal from entering the cecum in 50% of the treated mice. A maximumdosage of 30 mg./kg. was used. A result comparable to theplacebo-treated controls was reported as "N", i.e., inactive. Theresults are given in Table III.

ANTIDIARRHEAL

Compounds which were active in the antimotility test were then evaluatedin a secondary test which measured a counter-action on diarrhea. Thiswas another type of antimotility test adapted from that reported byJanssen in U.S. Pat. No. 3,539,579. In this test adult maleSwiss-Webster mice weighing 30 to 40 g. were employed, using 6 mice pertreatment. The test compound was administered orally in a dosage serieswith a maximum of 30 mg./kg. either in water if soluble or else in 0.5%methyl cellulose. One hour after treatment, each animal received asingle dose of 0.3 ml. of castor oil, administered orally. The animalswere then individually caged and provided food and water. Three hoursthereafter, the presence or absence of diarrhea was noted in allanimals. Ninety-nine percent of the control animals showed diarrhea. Theresults are reported in terms of an ED₅₀, i.e., the dosage in mg./kg.which inhibited diarrhea in 50% of the treated mice. If there were nochanges from the untreated controls, the result was reported as an "N",i.e., inactive as an antidiarrheal agent.

The results are included in Table III.

                  Table III                                                       ______________________________________                                        Antimotility Activity                                                         Preparation                                                                              Antimotility   Antidiarrheal                                                  ED.sub.50 (mg./kg. P.O.)                                                                     ED.sub.50 (mg./kg. P.O.)                            ______________________________________                                        A              11.5           7.8                                             B              >15            15-30                                           C              N              N                                               D              N              NT*                                             E              5.0            12.5                                            F              8.6            10.5                                            G              N              N                                               H              2.4            4.3                                             I              N              N                                               J              N              NT                                              K              7.2            <30                                             L              15-30          <30                                             M              7.4            15-30                                           N              <30            NT                                              O              18.5           >30                                             P              N              N                                               Q              N              N                                               R              12.5           30                                              S              6.4            <30                                             T              7.0            15-30                                           U              N              N                                               AA             <30            <30                                             AB             4.4            3.8                                             AC             <30            NT                                              AD             <30            NT                                              AE             N              NT                                              AF             N              NT                                              AG             13             10                                              AH             20             N                                               AI             15.5           11.5                                            AJ             30             NT                                              AK             15-30          N                                               AL             N              N                                               AM             N              N                                               AN             N              NT                                              AO             <30            N                                               AP             N              N                                               AQ             N              N                                               AR             N              N                                               atropine       9.8            >40                                             codeine        29             35                                               phosphate                                                                    Daricon        3.4            50                                              Lomotil        2              9.9                                             morphine sulfate                                                                             9.5            14                                              Pro-Banthine   14.7           inactive up                                                                   to 80                                           ______________________________________                                         NT = not tested                                                          

The compounds which were found to be active in the antimotility testsinclude:

2-CH₃ C.sub. 6 H₄ NHC(S)NHCH₂ CH₂ OH

2-C₂ H₅ C₆ H₄ NHC(S)NHCH₂ CH₂ OH

2,3-(CH₃)₂ C₆ H₃ NHC(S)NHCH₂ CH₂ OH

2,4-(CH₃)₂ C₆ H₃ NHC(S)NHCH₂ CH₂ OH

2,6-(CH₃)₂ C₆ H₃ NHC(S)NHCH₂ CH₂ OH

2-CH₃ -3-ClC₆ H₃ NHC(S)NHCH₂ CH₂ OH

2-CH₃ -4-ClC₆ H₃ NHC(S)NHCH₂ CH₂ OH

2-CH₃ -5-ClC₆ H₃ NHC(S)NHCH₂ CH₂ OH

2-CH₃ -6-ClC₆ H₃ NHC(S)NHCH₂ CH₂ OH

2-CH₃ -4-BrC₆ H₃ NHC(S)NHCH₂ CH₂ OH

2-CH₃ -4-CH₃ OC₆ H₃ NHC(S)NHCH₂ CH₂ OH

2,4,6-(CH₃)₃ C₆ H₂ NHC(S)NHCH₂ CH₂ OH

α-naphthylNHC(S)NHCH₂ CH₂ OH

2-CH₃ C₆ H₄ NHC(S)N(CH₃)₂

2,4-(CH₃)₂ C₆ H₃ NHC(S)N(CH₃)₂

2,6-(CH₃)₂ C₆ H₃ NHC(S)N(CH₃)₂

2-CH₃ -4-ClC₆ H₃ NHC(S)N(CH₃)₂

2,4-(CH₃)₂ C₆ H₃ NHC(S)NHCH₂ CH₂ NH₂

2,4-(CH₃)₂ C₆ H₃ NHC(S)NHCH₂ CH₂ N(CH₃)₂

2,6-(CH₃)₂ C₆ H₃ NHC(S)NHCH₂ CH₂ NH₂

2-CH₃ -4-ClC₆ H₃ NHC(S)NHCH₂ CH₂ NH₂

Certain antisecretory, antispasmodic or anticholinergic agents arecommonly used to control hypersecretion and hypermotility which may beassociated with gastrointestinal disorders, such as gastritis, pepticulcer, pylorospasm, and the like. Among these are atropine, codeinephosphate, oxyphencyclimine hydrochloride (Daricon), diphenoxylatehydrochloride (Lomotil, morphine sulfate and propantheline bromide(Pro-Banthine) which were used as standards in the above antisecretoryand antimotility evaluations. It will be noted that many of thethioureas of this invention are more active than these well knownstandards.

There are various types of diarrhea such as that caused bygastroenteritis, an irritable bowel, functional hypermotility,ulcerative colitis, food poisoning or acute infections. Severalantidiarrheal agents now in use include those containing narcotics suchas morphine, antibiotics such as neomycin, anticholinergic agents suchas oxyphencyclimine hydrochloride (Daricon) or propantheline bromide(Pro-Banthine), bacillus cultures such as Lactobacillus acidophilus,clays such as kaolin, and antimicrobials such as furazolidone, andantimotility agents such as diphenoxylate hydrochloride (Lomotil). Noneof these, however, are based on a thiourea derivative.

The compositions of the invention preferably contain 0.1-90% by weightof a compound of Formula I.

Compositions for oral administration are the preferred compositions ofthe invention, and these are the known pharmaceutical forms for suchadministration, such as for example tablets, capsules, syrups andaqueous and oily suspensions. The excipients used in the preparation ofthese compositions are the pharmaceutically acceptable excipients knownin the pharmacist's art.

Preferred compositions are tablets wherein a compound of general FormulaI is mixed with an inert diluent such as calcium phosphate in thepresence of disintegrating agents, e.g., maize starch, and lubricatingagents, e.g., magnesium stearate. Such tablets may, if desired, beprovided with enteric coatings by known methods, for example by the useof cellulose acetate phthalate. Similarly capsules, for example hard orsoft gelatin capsules, containing a compound of Formula I, with orwithout other excipients, may be prepared by conventional means and, ifdesired, provided with enteric coatings in a known manner. The tabletsand capsules may conveniently each contain 25-500 mg. of a compound ofgeneral Formula I. Other compositions for oral administration includefor example aqueous suspensions containing a compound of general FormulaI in aqueous media in the presence of a non-toxic suspending agent e.g.,sodium carboxymethylcellulose and dispersing agents, and oilysuspensions containing a compound of general Formula I in a vegetableoil for example arachis oil.

Compositions of the invention suitable for rectal administration are theknown pharmaceutical forms for such administration, such as for examplesuppositories with cocoa butter or polyethylene glycol bases.

Compositions of the invention suitable for parenteral administration arethe known pharmaceutical forms for such administration, for examplesterile suspensions in aqueous and oily media or sterile solutions inpropylene glycol.

The following examples are submitted by way of illustration but are notto be construed as limiting the invention.

EXAMPLE 1

A blend of 1-(2,6-dimethylphenyl)-3-(2-hydroxyethyl)thiourea (25 parts),corn starch (10 parts), calcium phosphate (20 parts), microcrystallinecellulose (44 parts) and magnesium stearate (1 part) is compressed in atabletting machine in a size to produce a tablet containing 50 mg. ofthe thiourea.

EXAMPLE 2

A blend of 50 parts of 1-(2-methylphenyl)-3-(2-hydroxyethyl)thiourea, 23parts of dextrose monohydrate, 23 parts of calcium phosphate and 4 partsof magnesium stearate is packaged into hard gelatine capsules so thateach capsule contains 75 mg. of the thiourea.

EXAMPLE 3

A blend of 50 parts of 1-(2-methyl-4-chlorophenyl)-3,3-dimethylthioureaand 50 parts of spray-dried skimmed milk powder is encapsulated inspherical soft gelatine capsules so that each capsule contains 25 mg. ofthe thiourea.

EXAMPLE 4

Suppositories weighing 1 g. and containing 100 mg. of1-(2,4-dimethylphenyl)-3-(2-dimethylaminoethyl)-thiourea are prepared ina conventional manner using a base of polyethylene glycol 4000 (33%),polyethylene glycol 6000 (47%) and water (20%).

The dosage requirement to achieve the antisecretory, antimotility orantidiarrheal effect in the mammal will vary with various factors suchas the species of animal, general health and tolerance of the animal,weight, sex and age of the animal, the nature and severity of thecondition being treated, and the like. Generally a total daily dosagewould be in the range of 1 to 25 mg. per kg. of body weight.Advantageously equal doses will be administered from one to six timesdaily.

Table IV gives the literature references for the known compounds andanalytical data for the novel compounds. The structures for thecompounds are given in Table I (supra).

                                      Table IV                                    __________________________________________________________________________    Identity of ArylNHC(S)NR.sup.1 R.sup.2 Structures                                                    Literature Reference or                                       Empirical                                                                             Melting Analysis                                               Preparation                                                                          Formula Point (°C.)                                                                    %C     %H    %N     %S                                 __________________________________________________________________________    A              124     French patent 1,356,908                                B      C.sub.11 H.sub.16 N.sub.2 OS                                                          131     58.6(58.9)                                                                           7.0(7.1)                                                                            12.4(12.5)                                                                           14.5(14.0)                         E      C.sub.11 H.sub.16 N.sub.2 OS                                                          137     58.8   7.3   12.5   14.4                               F              127     Maybridge Chemical Co. catalog                         H              129     French Patent 1,356,908                                K              140     French Patent 1,356,908                                L      C.sub.10 H.sub.13 ClN.sub.2 OS                                                        127     49.3(49.2)                                                                           5.5(5.6)                                                                            11.6(11.5)                                                                           13.3(13.1)                         M              135     Maybridge Chemical Co. catalog                         N      C.sub.10 H.sub.13 ClN.sub.2 OS                                                        95      49.5   5.2   11.5   13.1                               O      C.sub.10 H.sub.13 BrN.sub.2 OS                                                        146     41.9(41.5)                                                                           4.7(4.5)                                                                             9.7(9.6)                                                                            11.1(11.1)                         R      C.sub.11 H.sub.16 N.sub.2 O.sub.2 S                                                   176     54.6(55.0)                                                                           6.7(6.7)                                                                            11.6(11.7)                                                                           13.3(13.3)                         S      C.sub.12 H.sub.18 N.sub.2 OS                                                          132     60.7(60.5)                                                                           7.8(7.6)                                                                            11.9(11.8)                                T              168     French Patent 1,356,908                                AA             J. Pharmacool. Exptl. Therap.                                                                    168, 229 (1969)                             AB             161     C.A. 64,1906a (1966)                                   AC     C.sub.11 H.sub.16 N.sub.2 S                                                           154     63.0(63.4)                                                                           8.0(7.7)                                                                            13.3(13.5)                                                                           15.4(15.4)                         AD             170     French Patent 1,555,793                                AG     C.sub.11 H.sub.17 N.sub.3 S                                                           134     59.5(59.2)                                                                           7.7(7.6)                                                                            18.7(18.9)                                                                           14.7(14.3)                         AH     C.sub.13 H.sub.21 N.sub.3 S                                                           102     62.6(62.1)                                                                           8.6(8.3)                                                                            17.0(16.6)                                                                           12.5(12.7)                         AI             143     Bull. Soc. Chim. France 1951, 2114-26                  AJ     C.sub.10 H.sub.14 ClN.sub.3 S                                                         122     49.4(49.4)                                                                           5.5(5.8)                                                                            17.3(17.3)                                                                           13.4(13.2)                         __________________________________________________________________________     *Values are given as Found (calculated)                                  

These novel and useful thioureas belong to the class of compounds of thegeneral structure ##EQU4## wherein 1. when R¹ is hydrogen and R² is thegroup --CH₂ CH₂ Y wherein

Y is amino, dimethylamino or hydroxy,

Aryl is

a. 2-ethylphenyl,

b. 2,4,6-trimethylphenyl or

c. the group ##SPC1##

wherein X is 4-bromo, a 4-chloro or 6-chloro group, a 4-methoxy group ora 3-methyl group,

2. when R¹ is hydrogen and R² is the group --CH₂ CH₂ Y wherein

Y is amino or dimethylamino,

Aryl is 2,4-dimethylphenyl, or 2-methyl-4-chlorophenyl or

3. when R¹ and R² are methyl, Aryl is 2,6-dimethylphenyl.

What is claimed is:
 1. A method for treating a mammal suffering fromgastrointestinal disturbances which comprises administering to saidmammal in an amount effective to reduce gastrointestinal motility anddiarrhea, a compound of the formula: ##EQU5## wherein X¹ is methyl orethyl; X² is 3,4 or 6-methyl; 3,4 or 5-chloro or bromo and n is aninteger of 0-2.
 2. A method according to claim 1 wherein the compound is1-(2-ethylphenyl)-3-(2-hydroxyethyl)thiourea.
 3. A method according toclaim 1 wherein the compound is1-(2,3-dimethylphenyl)-3-(2-hydroxyethyl)thiourea.
 4. A method accordingto claim 1 wherein the compound is1-(2-methyl-4-chlorophenyl)-3-(2-hydroxyethyl)thiourea.
 5. A methodaccording to claim 1 wherein the compound is1-(2-methyl-4-bromophenyl-3-(2-hydroxyethyl)thiourea,
 6. A methodaccording to claim 1 wherein the compound is1-(2,4,6-trimethylphenyl)-3-(2-hydroxyethyl)thiourea.